Comparison of analytical-flow, micro-flow and nano-flow LC-MS/MS for sub-proteome analysis.

The accurate and sensitive analysis of sub-proteomic samples, such as host cell proteins (HCPs) in recombinant products and stem cells in medical devices, is crucial for ensuring product safety and efficacy in the biopharmaceutical industry. However, current analytical techniques, such as conventional analytical-flow LC-MS/MS, face limitations in sensitivity due to the low concentrations of target proteins and the complexity of the sample matrix. In this study, a highly sensitive and repeatable micro-flow LC-MS/MS strategy was developed by replacing analytical-flow tubing with micro-flow tubing on an existing analytical-flow LC-MS system for sub-proteomic sample analysis. Method optimization and evaluation were first conducted with monoclonal antibody (mAb) digestion, focusing on enhancing sensitivity and repeatability. Over 8 days, relative standard deviations (RSDs) for retention time and mass area were less than 5 % and 10 %, respectively. Sensitivity improved by 2.91-4.14 times compared to the analytical-flow LC-MS/MS method. After confirming the reliability of the method, the micro-flow LC-MS/MS method was compared to the nano-flow LC-MS/MS method and the analytical-flow LC-MS/MS method in sub-proteomic sample analysis. For HCPs, the micro-flow LC-MS/MS method demonstrated superior qualitative and much better reproducibility than the nano-flow LC-MS/MS method, with more than 98 % of proteins showing intensity RSD values below 20 %. In the analysis of mesenchymal stem cells (MSCs), the micro-flow method demonstrated good reproducibility and better sensitivity than the analytical-flow method. Taking the analysis of the 20th generation of MSC products as an example, the sample analyzed by micro-flow LC-MS/MS resulted in the identification of 68 % and 8.5 % more peptides and proteins, respectively. Moreover, micro-flow maintained stable system pressure while analyzing umbilical cord stem cells, where nano-flow methods often encounter blockages. This micro-flow LC-MS/MS method is notable for its sensitivity, reproducibility, and straightforward operation, making it highly adaptable for diverse sub-proteomic analyses in biopharmaceutical laboratories.

Prognostic prediction model for patients with pathological T1N0 stage esophageal squamous cell carcinoma undergone esophagectomy.

Background: There is a shortage of reliable predictive models to provide valuable prognostic information for early esophageal squamous cell carcinoma (ESCC) without lymph node metastasis (LNM). We aimed to develop and validate a nomogram using the prognostic factors in T1N0 ESCC patients. Methods: Patients with pathological T1N0 ESCC who underwent esophagectomy between 2014 and 2021 at three institutes were reviewed. The prognostic factors were evaluated by Cox proportional hazards model and a nomogram was developed. Patients were divided into high- and low-risk groups based on cut-off value of total points in the nomogram. Overall survival (OS) was estimated by the Kaplan-Meier method and compared using the log-rank test. Results: A total of 275 patients were included and split into training (n=180) and external validation (n=95) cohorts. In the training cohort, multivariable analysis showed that the surgical approach, T1 substage, and carcinoembryonic antigen (CEA) level were independent prognostic factors. The developed nomogram had relatively high performance, with the area under the receiver operating characteristic (ROC) curve (AUC) of 0.783, 0.711 and 0.612 for 1-, 3-, and 5-year OS, respectively. The calibration curves showed that the predicted probability was in good agreement with the actual probability. Forty-seven was determined as cut-off value of total points. High-risk group (n=148) showed a significant poor OS than low-risk group (n=127) (P<0.001). Conclusions: Left surgical approach, stage T1b, and higher CEA were associated with poorer prognosis in T1N0 ESCC patients. The nomogram demonstrated a good performance to predict the individual survival.

Regorafenib combined with immune checkpoint inhibitors versus regorafenib monotherapy as a late-line treatment for metastatic colorectal cancer: a single-center, retrospective cohort study.

Background: Few data are available on metastatic colorectal cancer (mCRC) treated with late-line regorafenib monotherapy or combined with other therapies. This study thus aimed to examine regorafenib combined with immune checkpoint inhibitors (ICIs) compared with regorafenib monotherapy in patients with advanced CRC. Methods: This single-center retrospective cohort study included patients with advanced CRC who experienced recurrence and progression after standard first- and second-line treatments treatment from November 2018 to December 2021. The patients received regorafenib plus ICIs or regorafenib monotherapy. Treatment response was evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST). Overall survival (OS) and progression-free survival (PFS) were analyzed via multivariate analysis. Results: The combined group and the monotherapy group included 30 and 43 patients, respectively. The median OS (13.7 vs. 10.1 months; P=0.10) and PFS (4 vs. 3.6 months; P=0.32) were not significantly different between the two groups. In males, the median OS was significantly longer in the combined group compared with the monotherapy group (not reached vs. 8.03 months; P=0.02), but the median PFS showed no significant difference (7.23 vs. 3.90 months; P=0.16). There was no significant difference in OS (P=0.71) or PFS (P=0.89) in females. Eastern Cooperative Oncology Group performance status (ECOG PS) 1 [vs. 0; hazard ratio (HR) =3.13, 95% confidence interval (CI): 1.61-6.10; P<0.001] was independently associated with PFS. ECOG PS 1 (vs. 0; HR =3.63, 95% CI: 1.54-8.56; P=0.003) and combined therapy (vs. monotherapy; HR =0.47, 95% CI: 0.22-0.99; P=0.048) were associated with OS. Conclusions: Regorafenib combined with ICIs led to numerically longer PFS and significantly prolonged OS in patients with mCRC compared to regorafenib monotherapy, especially in male patients.

Phosphorylated vimentin-triggered fibronectin matrix disaggregation enhances the dissemination of Treponema pallidum subsp. pallidum across the microvascular endothelial barrier.

Fibronectin (FN) is an essential component of the extracellular matrix (ECM) that protects the integrity of the microvascular endothelial barrier (MEB). However, Treponema pallidum subsp. pallidum (Tp) breaches this barrier through elusive mechanisms and rapidly disseminates throughout the host. We aimed to understand the impact of Tp on the surrounding FN matrix of MEB and the underlying mechanisms of this effect. In this study, immunofluorescence assays (IF) were conducted to assess the integrity of the FN matrix surrounding human microvascular endothelial cell-1 (HMEC-1) with/without Tp co-culture, revealing that only live Tp exhibited the capability to mediate FN matrix disaggregation in HMEC-1. Western blotting and IF were employed to determine the protein levels associated with the FN matrix during Tp infection, which showed the unaltered protein levels of total FN and its receptor integrin α5ß1, along with reduced insoluble FN and increased soluble FN. Simultaneously, the integrin α5ß1-binding protein-intracellular vimentin maintained a stable total protein level while exhibiting an increase in the soluble form, specifically mediated by the phosphorylation of its 39th residue (pSer39-vimentin). Besides, this process of vimentin phosphorylation, which could be hindered by a serine-to-alanine mutation or inhibition of phosphorylated-AKT1 (pAKT1), promoted intracellular vimentin rearrangement and FN matrix disaggregation. Moreover, within the introduction of additional cellular FN rather than other Tp-adhered ECM protein, in vitro endothelial barrier traversal experiment and in vivo syphilitic infectivity test demonstrated that viable Tp was effectively prevented from penetrating the in vitro MEB or disseminating in Tp-challenged rabbits. This investigation revealed the active pAKT1/pSer39-vimentin signal triggered by live Tp to expedite the disaggregation of the FN matrix and highlighted the importance of FN matrix stability in syphilis, thereby providing a novel perspective on ECM disruption mechanisms that facilitate Tp dissemination across the MEB.

A modified GLIM criteria-based nomogram for the survival prediction of gastric cancer patients undergoing surgical resection.

BACKGROUND: This study aimed to develop a comprehensive model based on five GLIM variables to predict the individual survival and provide more appropriate patient counseling. METHODS: This retrospective cohort study included 301 gastric cancer (GC) patients undergoing radical resection. C-reactive protein (CRP) as an inflammatory marker was included in GLIM criteria and a nomogram for predicting 5-year overall survival (OS) in GC patients was established. The Bootstrap repeated sampling for 1000 times was used for internal validation. RESULTS: Of the total 301 patients, 20 (6.64%) died within 5 years. CRP improved the sensitivity and accuracy of the survival prediction model (AUC = 0.782, 0.694 to 0.869 for the model without CRP; AUC = 0.880, 0.809 to 0.950 for the model adding CRP). Besides, a GLIM-based nomogram was established with an AUC of 0.889. The C-index for predicting OS was 0.878 (95% CI: 0.823 to 0.934), and the calibration curve fitted well. Decision curve analysis (DCA) showed the clinical utility of the nomogram based on GLIM. CONCLUSION: The addition of CRP improved the sensitivity and accuracy of the survival prediction model. The 5-year survival probability of GC patients undergoing radical resection can be reliably predicted by the nomogram presented in this study.

Unintentionally-produced persistent organic pollutants in the aquatic environment contaminated from historical chlor-alkali production.

Historical chlor-alkali production has led to substantial concentrations of persistent organic pollutant residues in the environment. This study systematically investigated the distribution of polycyclic aromatic hydrocarbons (PAHs), chlorinated/brominated-PAHs (Cl/Br-PAHs), polychlorinated naphthalenes (PCNs), and hexachlorobutadiene (HCBD) in sediment, lotus (Nelumbo nucifera), and fish samples from Ya-Er Lake, which is a site in China with historical chlor-alkali contamination. The average concentrations [(4.97-1.47) × 103 ng/g dry weight (dw)] of these pollutants in backfill sediments, which were dredged from the lake after chlor-alkali production stopped, were 2.68-70.87 times those in fresh lake sediments (0.622-218 ng/g dw) and reported concentrations in other areas. Correlation analyses indicated that Cl-PAHs, Br-PAHs, and PCNs likely originated from halogenation of parent PAHs in the study area, and the chlorination ratios were larger than those of bromination. The Cl(1/2/3)-PAHs/PAHs and Br(1)-PAHs/PAHs ratios were higher than those for PAHs with more halogen atoms. This contamination extended into the biota, with notable pollutant burdens found in lotus (Nelumbo nucifera, 0.305-77.3 ng/g dw) and even higher concentrations in fish (2.20-345 ng/g lipid weight). Estimated biological soil accumulation factors revealed significant enrichment in lotus organs (mean: 7.19) and fish muscle (mean: 10.65), especially the latter, which highlighted bioaccumulation and potential food chain transfer risks. The estimated daily intakes of PAHs, Cl/Br-PAHs, and HCBD through fish consumption currently pose negligible risks, while dietary intake of PCNs may present health concerns. Continuous monitoring and impact assessments are crucial for developing appropriate risk management strategies to safeguard public health.

Phenotypic changes and gene expression profiles of Vibrio parahaemolyticus in response to low concentrations of ampicillin.

Vibrio parahaemolyticus is a leading cause of seafood-associated gastroenteritis and possesses intrinsic resistance to ampicillin. While ampicillin can trigger transcriptional responses of global genes, the behavioral and molecular changes that occur in V. parahaemolyticus when exposed to ampicillin are not fully understood. In this work, we investigated the effects of low concentrations of ampicillin on the physiology and gene expression of V. parahaemolyticus by combining phenotypic assays and RNA sequencing (RNA-seq) analysis. Our results showed that the growth of V. parahaemolyticus were notably delayed, and both motility and c-di-GMP production were significantly inhibited in the response to low concentrations of ampicillin stress. In contrast, biofilm formation by V. parahaemolyticus was enhanced by exposure to low concentrations of ampicillin. However, low concentrations of ampicillin had no effect on the cytotoxicity or adherence activity of V. parahaemolyticus. The RNA-seq data revealed that a low concentration of ampicillin significantly affected the expression levels of 676 genes, including those involved in antibiotic resistance, virulence, biofilm formation, and regulation. This work contributes to our understanding of how V. parahaemolyticus alters its behavior and gene expression in response to ampicillin exposure.

GefB, a GGDEF domain-containing protein, affects motility and biofilm formation of Vibrio parahaemolyticus and is regulated by quorum sensing regulators.

Vibrio parahaemolyticus (V. parahaemolyticus) stands as the predominant etiological agent responsible for gastroenteritis associated with the consumption of seafood. Cyclic di-guanosine monophosphate (c-di-GMP), a secondary messenger in bacteria, controls multiple bacterial behaviors including pathogenesis, the development of biofilms, and motility. The protein GefB (VPA1478), characterized by the presence of a GGDEF domain, inhibits the swarming motility of V. parahaemolyticus. In this study, we showed that deletion of gefB remarkably reduced cellular c-di-GMP level and biofilm formation by V. parahaemolyticus, but significantly enhanced the swimming and swarming motility. In addition, GefB inhibited the polar and lateral flagellar genes but activated genes associated with exopolysaccharide production of V. parahaemolyticus. The data also demonstrated that vpa1477 and gefB are co-transcribed as a single transcriptional unit, designated as vpa1477-gefB. Transcription of vpa1477-gefB was under the collective regulation of the master quorum sensing (QS) regulators AphA and OpaR, which function at low (LCD) and high cell density (HCD), respectively. AphA positively regulated vpa1477-gefB transcription at LCD, whereas OpaR negatively regulated its transcription at HCD. The findings significantly enhance our comprehension of the metabolism and regulatory mechanisms of c-di-GMP in V. parahaemolyticus.

Human α-synuclein aggregation activates ferroptosis leading to parvalbumin interneuron degeneration and motor learning impairment.

The accumulation of α-synuclein induces neuronal loss in midbrain nuclei and leads to the disruption of motor circuits, while the pathology of α-synuclein in cortical regions remains elusive. To better characterize cortical synucleinopathy, here we generate a mouse model with the overexpression of human α-synuclein in the primary motor cortex (M1) of mice. A combination of molecular, in vivo recording, and behavioral approaches reveal that cortical expression of human α-synuclein results in the overexcitation of cortical pyramidal neurons (PNs), which are regulated by the decreased inhibitory inputs from parvalbumin-interneurons (PV-INs) to impair complex motor skill learning. Further mechanistic dissections reveal that human α-synuclein aggregation activates ferroptosis, contributing to PV-IN degeneration and motor circuit dysfunction. Taken together, the current study adds more knowledge to the emerging role and pathogenic mechanism of ferroptosis in neurodegenerative diseases.

Characteristics of soil microplastics and ecological risks in the Qilian Mountains region, Northeast Tibetan Plateau.

Microplastics (MPs) pollution has become a vital global environmental issue. However, comprehensive understanding of the ecological risks of MPs in soils of Northeast Tibetan Plateau still requires further study. In this study, we used the Agilent 8700 Laser Direct Infrared (LDIR) spectroscopy to analyze the characteristics of 10-1000 µm MPs in soils of different vegetation types throughout the Qilian Mountains basin, and to comprehensively explore the ecological risks of MPs in various ecological environments. The results indicate that MPs abundance is highest in soil of shrub areas (26,369 ± 32,147 items kg-1-dry weight (dw)), followed by woodland (22,215 ± 22,544 items kg-1-dw), desert (17,769 ± 9,040 items kg-1-dw), grassland (16,462 ± 12,872 items kg-1-dw), and forest (15,662 ± 13,857 items kg-1-dw). MPs in soils of different vegetation types show similar physical and chemical characteristics, with the shape dominated by fragments (93%-96%), followed by fibers and a few beads, with dominant sizes of 10-30 µm (63%-76%), and polymers dominated by polyamide (PA) and polyethylene terephthalate (PET). Additionally, the environmental risks posed by the fundamental characteristics of MPs have been quantified through the Pollution Load Index (PLI), Pollution Hazard Index (PHI), and Potential Ecological Risk Index (PERI) models. According to the PLI assessment, the current levels of MPs in the environment have not yet imposed significant burdens on the ecosystem. However, the results of PHI and PERI indicate a higher risk of MPs pollution in the Qilian Mountains. This study offers vital information for MPs pollution in the whole Qilian Mountains regions and their potential environmental risks in remote areas' soil.

Identification and analysis of imprinted genes in wild strawberry uncover a regulatory pathway in endosperm development.

Fertilization is a fundamental process that triggers seed and fruit development, but the molecular mechanisms underlying fertilization-induced seed development are poorly understood. Previous research has established AGamous-Like62 (AGL62) activation and auxin biosynthesis in the endosperm as key events following fertilization in Arabidopsis (Arabidopsis thaliana) and wild strawberry (Fragaria vesca). To test the hypothesis that epigenetic mechanisms are critical in mediating the effect of fertilization on the activation of AGL62 and auxin biosynthesis in the endosperm, we first identified and analyzed imprinted genes from the endosperm of wild strawberry. We isolated endosperm tissues from F1 seeds of two wild strawberry Fragaria vesca subspecies, generated endosperm-enriched transcriptomes, and identified candidate Maternally-Expressed and Paternally-Expressed Genes (MEGs and PEGs). Through bioinformatic analyses, we identified four imprinted genes that may be involved in regulating the expression of FveAGL62 and auxin biosynthesis genes. We conducted functional analysis of a maternally expressed gene FveMYB98 through CRISPR-knockout and overexpression in transgenic strawberry as well as analysis in heterologous systems. FveMYB98 directly repressed FveAGL62 at stage 3 endosperm, which likely serves to limit auxin synthesis and endosperm proliferation. These results provide an inroad into the regulation of early stage seed development by imprinted genes in strawberry, suggest potential function of imprinted genes in parental conflict, and identify FveMYB98 as a regulator of a key transition point in endosperm development.

Proteome and Phosphoproteome Profiling Reveal the Toxic Mechanism of Clostridium perfringens Epsilon Toxin in MDCK Cells.

Epsilon toxin (ETX), a potential agent of biological and toxic warfare, causes the death of many ruminants and threatens human health. It is crucial to understand the toxic mechanism of such a highly lethal and rapid course toxin. In this study, we detected the effects of ETX on the proteome and phosphoproteome of MDCK cells after 10 min and 30 min. A total of 44 differentially expressed proteins (DEPs) and 588 differentially phosphorylated proteins (DPPs) were screened in the 10 min group, while 73 DEPs and 489 DPPs were screened in the 30 min group. ETX-induced proteins and phosphorylated proteins were mainly located in the nucleus, cytoplasm, and mitochondria, and their enrichment pathways were related to transcription and translation, virus infection, and intercellular junction. Meanwhile, the protein-protein interaction network screened out several hub proteins, including SRSF1/2/6/7/11, SF3B1/2, NOP14/56, ANLN, GTPBP4, THOC2, and RRP1B. Almost all of these proteins were present in the spliceosome pathway, indicating that the spliceosome pathway is involved in ETX-induced cell death. Next, we used RNAi lentiviruses and inhibitors of several key proteins to verify whether these proteins play a critical role. The results confirmed that SRSF1, SF3B2, and THOC2 were the key proteins involved in the cytotoxic effect of ETX. In addition, we found that the common upstream kinase of these key proteins was SRPK1, and a reduction in the level of SRPK1 could also reduce ETX-induced cell death. This result was consistent with the phosphorylated proteomics analysis. In summary, our study demonstrated that ETX induces phosphorylation of SRSF1, SF3B2, THOC2, and SRPK1 proteins on the spliceosome pathway, which inhibits normal splicing of mRNA and leads to cell death.

PDIA3 defines a novel subset of adipose macrophages to exacerbate the development of obesity and metabolic disorders.

Adipose tissue macrophages (ATMs) play important roles in maintaining adipose tissue homeostasis and orchestrating metabolic inflammation. Given the extensive functional heterogeneity and phenotypic plasticity of ATMs, identification of the authentically pathogenic ATM subpopulation under obese setting is thus necessitated. Herein, we performed single-nucleus RNA sequencing (snRNA-seq) and unraveled a unique maladaptive ATM subpopulation defined as ATF4hiPDIA3hiACSL4hiCCL2hi inflammatory and metabolically activated macrophages (iMAMs), in which PDIA3 is required for the maintenance of their migratory and pro-inflammatory properties. Mechanistically, ATF4 serves as a metabolic stress sensor to transcribe PDIA3, which then imposes a redox control on RhoA activity and strengthens the pro-inflammatory and migratory properties of iMAMs through RhoA-YAP signaling. Administration of Pdia3 small interfering RNA (siRNA)-loaded liposomes effectively repressed adipose inflammation and high-fat diet (HFD)-induced obesity. Together, our data support that strategies aimed at targeting iMAMs by suppressing PDIA3 expression or activity could be a viable approach against obesity and metabolic disorders in clinical settings.

Prediction of chemical-induced acute toxicity using in vitro assay data and chemical structure.

Exposure to various chemicals found in the environment and in the context of drug development can cause acute toxicity. To provide an alternative to in vivo animal toxicity testing, the U.S. Tox21 consortium developed in vitro assays to test a library of approximately 10,000 drugs and environmental chemicals (Tox21 10 K compound library) in a quantitative high-throughput screening (qHTS) approach. In this study, we assessed the utility of Tox21 assay data in comparison with chemical structure information in predicting acute systemic toxicity. Prediction models were developed using four machine learning algorithms, namely Random Forest, Naïve Bayes, eXtreme Gradient Boosting, and Support Vector Machine, and their performance was assessed using the area under the receiver operating characteristic curve (AUC-ROC). The chemical structure-based models as well as the Tox21 assay data demonstrated good predictive power for acute toxicity, achieving AUC-ROC values ranging from 0.83 to 0.93 and 0.73 to 0.79, respectively. We applied the models to predict the acute toxicity potential of the compounds in the Tox21 10 K compound library, most of which were found to be non-toxic. In addition, we identified the Tox21 assays that contributed the most to acute toxicity prediction, such as acetylcholinesterase (AChE) inhibition and p53 induction. Chemical features including organophosphates and carbamates were also identified to be significantly associated with acute toxicity. In conclusion, this study underscores the utility of in vitro assay data in predicting acute toxicity.

The renewed tin-weighting treatment as sustainable and durable flame-retardant approach for protein silk fabric.

The facile development of a sustainable and durable flame-retardant approach for protein silk is of interest. Inspired by silk tin-weighting technology, this study developed a novel and sustainable in-situ deposition strategy based on biomass phytic acid to impart durable flame-retardant performance to silk fabrics. The chemical structure of insoluble chelating precipitation, and the surface morphology, thermal stability, combustion behavior, flame-retardant capacity, laundering resistance, and flame-retardant mode of action of the tin-weighting silk samples, were explored. The Sn-, P-, Si-containing insoluble chelating precipitation formed within the fiber interior and combined with silk fibers through electrostatic attraction and metal salt chelation. As a result, the tin-weighting silk displayed excellent self-extinguishing capacity, with the damaged length reduced to 9.2 cm and the LOI increased to 31.6 %; it also achieved self-extinguishing after 30 washing cycles, demonstrating high flame-retardant efficacy and laundering resistance. Moreover, the tin-weighting silk also showed the obvious suppression in smoke and heat generation by 55.6 % and 35.7 %, respectively. The synergistic charring action of phosphate groups, tin metal salts, and silicates was beneficial for enhancing the fire safety of silk. The tin-weighting treatment also displayed a minor impact on mechanical performance of silk fabrics.

Association between cardiometabolic index and congestive heart failure among US adults: a cross-sectional study.

Background: The risk of congestive heart failure (CHF) is significantly affected by obesity. However, data on the association between visceral obesity and the risk of CHF remain limited. We explored the relationship between CHF and cardiometabolic index (CMI). Methods: Drawing from the National Health and Nutrition Examination Survey (NHANES) for 2011-2018, we enrolled 9,008 participants in a cross-sectional study. We calculated the CMI as triglyceride (TG)/high density lipid-cholesterol (HDL-C) × weight-to-height ratio (WHtR), and CMI-age as CMI × age. Then, we analyzed CMI and CMI-age as categorical and continuous variables to assess its correlation with CHF. To assess the relationships of CMI and CMI-age with CHF, we used multiple logistic regression models and performed subgroup analysis. To examine the predictive ability of CMI and CMI-age on patients with CHF, we used receiver operating characteristic (ROC) curves. Results: The overall prevalence of CHF was 3.31%. The results revealed significant differences in demographic data, comorbidities, lifestyle variables, standing height, BMI, WC, WHtR, TG, and HDL-C among the four groups classified by CMI quartile and CMI-age quartile. When indicators were analyzed as continuous variables, CMI and CMI-age showed positive correlations with CHF in both the crude and adjusted models (all P < 0.05). When indicators were analyzed as categorical variables, it was found that in all four models, the ORs of group Q4 was significantly different compared to Q1 (all P < 0.05), suggesting the risk of CHF is significantly increased with higher CMI, and CMI-age. The associations of CMI and CMI-age with CHF were similar in all stratified populations (P for interaction > 0.05). The areas under the ROC curve (AUCs) of CMI and CMI-age in predicting CHF were 0.610 (95% CI, 0.578-0.642) and 0.697 (95% CI, 0.668-0.725) separately, suggesting that CMI-age was significantly better than the CMI in predicting CHF (P < 0.001). Conclusions: Both CMI and CMI-age were independently correlated with the risk for CHF. These results suggested that the CMI-age, which provides new insights into the prevention and management of CHF. CMI-age could serve as effective tools to identify CHF during primary care examinations and in medically resource-limited areas.

Efficacy and safety of camrelizumab plus apatinib in patients with advanced esophageal squamous cell carcinoma previously treated with immune checkpoint inhibitors (CAP 02 Re-challenge): A single-arm, phase II study.

BACKGROUND: With the increasing use of immune checkpoint inhibitors (ICIs) in advanced esophageal squamous cell carcinoma (ESCC), there remains an unmet need for options to address disease progression after prior ICIs. This single-arm phase II study evaluated the efficacy and safety of re-challenge with camrelizumab plus apatinib in patients with advanced ESCC who were previously treated with ICIs. METHODS: This study enrolled patients aged 18-75 years with unresectable locally advanced, locally recurrent, or distant metastatic ESCC who received prior ICIs. Patients received intravenous camrelizumab 200 mg every 2 weeks and oral apatinib 250 mg daily until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was the investigator-assessed confirmed objective response rate (ORR). RESULTS: Between September 1, 2021 and March 29, 2023, 49 eligible patients were enrolled and received treatment. Among the 49 patients, the confirmed ORR was 10.2 % (95 % CI 3.4-22.2), the disease control rate (DCR) was 69.4 % (54.6-81.7), the median progression-free survival (PFS) was 4.6 months (95 % CI 3.8-6.5) and overall survival (OS) was 7.5 months (5.5-13.6). Grade ≥ 3 treatment-related adverse events occurred in 17 patients (34.7 %). No treatment-related deaths occurred. CONCLUSIONS: This study showed that the confirmed ORR was modest and did not reach clinically meaningful improvement for patients with ESCC who were previously treated with ICIs, with a manageable safety profile.

Microplastics in glaciers of Tibetan Plateau: Characteristics and potential sources.

Microplastics (MPs) in glaciers of remote areas are a hot topic linking the global transport of atmospheric MPs. The Tibetan Plateau (TP) holds large volume of glaciers, providing an effective way to trace MPs transport. Moreover, MPs in glaciers may have adverse effects on the local ecosystem and human health. In this study, we investigate MPs in snowpits collected from six glaciers across the different domain of the TP. The average abundance of MPs in six snowpits is 339.22 ± 51.85 items L-1 (with size ≥10 µm) measured by Agilent 8700 Laser Direct Infrared Chemical Imaging System (LDIR), represented by relatively high MPs abundance in the southern TP and low in the northern TP. The polymers with lower density, namely polyethylene (PE), polyamide (PA), and rubber, are the main MPs types, which are predominated by fragments with sizes smaller than 100 µm in each snowpit. Sources of MPs on glaciers include local tourism and vehicle traffic emissions of MPs. Meanwhile, long-range atmospheric transport of MPs from surrounded regions cannot be ignored. Backward trajectory analysis indicates cross-boundary transport of atmospheric MPs from South Asia play an important role on MPs deposited onto TP glaciers. Analysis further reveals that MPs in glaciers are associated with atmospheric mineral dust deposition. This study provides new data for the investigation of MPs in glaciers of remote areas, and a reference for studying MPs in the ice cores of TP glaciers.

Effects of motor imagery-based brain-computer interface-controlled electrical stimulation on lower limb function in hemiplegic patients in the acute phase of stroke: a randomized controlled study.

Background: Lower limb motor dysfunction is one of the most serious consequences of stroke; however, there is insufficient evidence for optimal rehabilitation strategies. Improving lower limb motor function through effective rehabilitation strategies is a top priority for stroke patients. Neuroplasticity is a key factor in the recovery of motor function. The extent to which neuroplasticity-based rehabilitation therapy using brain-computer interface (BCI) is effective in treating lower limb motor dysfunction in acute ischemic stroke patients has not been extensively investigated. Objective: This study aimed to assess the impact of BCI rehabilitation on lower limb motor dysfunction in individuals with acute ischemic stroke by evaluating motor function, walking ability, and daily living activities. Methods: This study was conducted in a randomized controlled trial, involving 64 patients with acute ischemic stroke who experienced lower limb motor dysfunction. All patients were divided into two groups, with 32 patients assigned to the control group was given conventional rehabilitation once a day for 70 min, 5 times a week for 2 weeks, and the experimental group (n = 32) was given BCI rehabilitation on top of the conventional rehabilitation for 1 h a day, 30 min of therapy in the morning and an additional 30 min in the afternoon, for a total of 20 sessions over a two-week period. The primary outcome was lower extremity motor function, which was assessed using the lower extremity portion of the Fugl-Meyer Rating Scale (FMA-LE), and the secondary endpoints were the Functional Ambulation Scale (FAC), and the Modified Barthel index (MBI). Results: After 20 sessions of treatment, both groups improved in motor function, walking function, and activities of daily living, and the improvements in FMA-LE scores (p < 0.001), FAC (p = 0.031), and MBI (p < 0.001) were more pronounced in the experimental group compared with the control group. Conclusion: Conventional rehabilitation therapy combined with BCI rehabilitation therapy can improve the lower limb motor function of hemiplegic patients with stroke, enhance the patient's ability to perform activities of daily living, and promote the improvement of walking function, this is an effective rehabilitation policy to promote recovery from lower extremity motor function disorders.

Diabetic peripheral neuropathy based on Schwann cell injury: mechanisms of cell death regulation and therapeutic perspectives.

Diabetic peripheral neuropathy (DPN) is a complication of diabetes mellitus that lacks specific treatment, its high prevalence and disabling neuropathic pain greatly affects patients' physical and mental health. Schwann cells (SCs) are the major glial cells of the peripheral nervous system, which play an important role in various inflammatory and metabolic neuropathies by providing nutritional support, wrapping axons and promoting repair and regeneration. Increasingly, high glucose (HG) has been found to promote the progression of DPN pathogenesis by targeting SCs death regulation, thus revealing the specific molecular process of programmed cell death (PCD) in which SCs are disrupted is an important link to gain insight into the pathogenesis of DPN. This paper is the first to review the recent progress of HG studies on apoptosis, autophagy, pyroptosis, ferroptosis and necroptosis pathways in SCs, and points out the crosstalk between various PCDs and the related therapeutic perspectives, with the aim of providing new perspectives for a deeper understanding of the mechanisms of DPN and the exploration of effective therapeutic targets.